title: CR1 is associated with amyloid plaque burden and age-related cognitive decline.
abstract: OBJECTIVE
  Recently, genome-wide association studies have identified 3 new susceptibility loci for Alzheimer's disease (AD), CLU, CR1, and PICALM. We leveraged available neuropsychological and autopsy data from 2 cohort studies to investigate whether these loci are associated with cognitive decline and AD neuropathology.
  
  
  METHODS
  The Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP) are longitudinal studies that enroll nondemented subjects and include annual clinical evaluations and brain donation at death. We evaluated CR1 (rs6656401), CLU (rs11136000), and PICALM (rs7110631) in 1,666 subjects. We evaluated associations between genotypes and rate of change in cognitive function as well as AD-related pathology. Lastly, we used pathway analysis to determine whether relationships between single nucleotide polymorphisms and cognitive decline are mediated through AD pathology.
  
  
  RESULTS
  Among our study cohort, the mean years of follow-up were 7.8 for ROS and 4.3 for MAP. Only the CR1 locus was associated with both global cognitive decline (p = 0.011) and global AD pathology (p = 0.025). More specifically, the locus affects the deposition of neuritic amyloid plaque (p = 0.009). In a mediation analysis, controlling for amyloid pathology strongly attenuated the effect of the CR1 locus on cognitive decline.
  
  
  CONCLUSIONS
  We found that common variation at the CR1 locus has a broad impact on cognition and that this effect is largely mediated by an individual's amyloid plaque burden. We therefore highlight 1 functional consequence of the CR1 susceptibility allele and generalize the role of this locus to cognitive aging in the general population.
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Lori B
authors.initials: LB
authors.lastname: Chibnik
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Shulman
authors.forename: Sue E
authors.initials: SE
authors.lastname: Leurgans
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.forename: Robert S
authors.initials: RS
authors.lastname: Wilson
authors.forename: Dong
authors.initials: D
authors.lastname: Tran
authors.forename: Cristin
authors.initials: C
authors.lastname: Aubin
authors.forename: Aron S
authors.initials: AS
authors.lastname: Buchman
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Heward
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Myers
authors.forename: John A
authors.initials: JA
authors.lastname: Hardy
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Corneveaux
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
authors.forename: Denis A
authors.initials: DA
authors.lastname: Evans
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000704:Analysis of Variance; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003072:Cognition Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D058225:Plaque, Amyloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D017463:Receptors, Complement 3b / Q000235:genetics* / Q000378:metabolism
chemical_list: C509991:CR1 protein, human; D017463:Receptors, Complement 3b